The invention relates to methods of treating interstitial cystitis. 2. Description of the Prior Art
Interstitial cystitis is a chronic disease of the bladder which affects principally females between 30 and 70 years of age and involves a multitude of urinary and psychiatric complaints such as suprapubic pain on bladder filling, urinary frequency, urinary urgency, dysuria, a sensation of incomplete voiding, malaise, depression and anxiety, among others. The disease is sometimes characterized as "an irritable bladder in an irritable patient."
Histopathalogic examination of bladder biopsy specimens in patients with suspected interstitial cystitis is often used to rule out other diseases (e.g., carcinoma). Typical histopathalogic findings in interstitial cystitis include a non-specific inflammatory reaction, edema and vasodilatation in the submucosa, with or without detrusor fibrosis depending on the stage of the disease. A significant increase in the number of mast cells in the bladder lining, mainly in the detrusor muscle layer, is evident, and the histamine content of the bladder wall is significantly increased. See, e.g., E. M. Meares, Urology (Supplement), vol. 29, pp. 46-48 (1987 ); W. L. Lynes et al., J. Urology, vol. 138pp. 746-52 (1987); and J. Kastrup et al., Brit. J. Urology, vol. 55, pp. 495-500 (1983).
Recent studies indicate that the type of mast cells present in inflammatory bladder conditions such as interstitial cystitis may be of a special type know as mucosal mast cells, which are differentiated morphologically and histochemically from mast cells found, for example, in connective tissue. See J. Cornish et al., Int. Archs. Allergy Appl. Immun., vol. 81 , pp. 337-42 (1986).
The progressive effects of interstitial cystitis on patients are severe and debilitating. Urinary frequency, urgency and pain, among other classic symptoms, impact dramatically and adversely on the patients' quality of life and drive them to seek any possible treatment to alleviate this disorder.
Various drug treatments have been attempted for interstitial cystititis including the oral administration of steroids, antihistamines, anticholinergics, antispasmodices, non-steroidal anti-inflammatory agents, tranquilizers and narcotics. More recently, oral sodium pentosanpolysulfate (Elmiron) has been used in clinical trials to treat interstitial cystitis with mixed results. While some studies reported that a significant number of patients benefited form Elmiron treatment, e.g., A. Fritjoffson et al., J. Urology, vol. 138, pp. 507-12 (1987) and C. L. Parsons et al., J. Uroloqy, vol. 138, pp. 513-16 (1987), at least one double-blind, controlled trial found no statistically or clinically significant effect of Elmiron in comparison with placebo, M. Holm-Bentzen et al., J. Uroloqy, vol. 138, pp. 503-07 (1987). A significant drawback of oral Elmiron therapy for interstitial cystitis is the fact that the drug is primarily liver-metabolized and excreted only to the extent of about 4% in the urine. This means that only a small portion of the drug ingested actually reaches the disease site in the bladder. Furthermore, Elmiron has a relatively short duration of action and must be taken three or four times daily to achieve even the level of symptomatic relief shown in some studies.
Dimethyl sulfoxide (DMSO) has been utilized to a significant degree in the treatment of interstitial cystitis, primarily through intravesical injection of a 50% solution. The DMSO is usually administered initially every two weeks for a total of four to six treatments. After this initial course, intermittent treatments are given if and when symptoms recur.
There are a number of undesirable aspects of intravesical DMSO treatment. The procedure involves substantial discomfort and inconvenience for the patient, requiring the anesthetization of the urethra, insertion of a urethral catheter, emptying of the bladder and instilling of the DMSO into the bladder before removing the catheter. In addition, some patients experience a pronounced sensation of urethral burning during voiding after DMSO treatment and most patients experience a garlic-like odor to their breath and a similar taste in their mouths for 24 hours or more. A smaller number of patients complain of bladder spasms and irritability after DMSO treatments. See G. R. Sant, Urology (Supplement), vol. 29, pp. 17-21 (1987). According to Sant, intravesical DMSO results in satisfactory symptomatic improvement in only about 66 to 71% of patients, and in most patients no significant improvement in bladder capacity or endoscopic appearance of the bladder is reported.
Other modalities of treatment for interstitial cystitis have been utilized, including subcutaneous and intravesical injection of heparin, intravesical injection of silver nitrate and bladder distension. To the present date, no method of treatment or pharmaceutical agent for interstitial cystitis has been developed which provides safe and effective symptomatic relief with few adverse side effects and little patient discomfort. Indeed, none of the treatment modalities currently employed even provide symptomatic relief to patients on a consistent basis, apart from the expense, discomfort and inconvenience which they entail.